Dataset Information

Cocaine Seeking During Initial Abstinence Is Driven by Noradrenergic and Serotonergic Signaling in Hippocampus in a Sex-Dependent Manner.

ABSTRACT: There is evidence for sex differences in cocaine addiction from both clinical and preclinical studies. In particular, preclinical studies indicate that females may be more sensitive than males to stress-induced drug seeking. The dorsal hippocampus (DH) is prominently involved in the stress response, as are the locus coeruleus norepinephrine (LC-NE) and dorsal raphe serotonin (DR 5-HT) systems. Moreover, DH receives strong inputs from LC-NE and DR 5-HT neurons. We hypothesized that the stress associated with non-reinforced drug seeking during early abstinence (on extinction day 1 (ED1)) may contribute to drug seeking via ?-adrenergic and 5-HT neurotransmission in DH. We observed decreased drug-seeking behavior on ED1 following 10?mg/kg S-propranolol (?-adrenergic and 5-HT1A/1B receptor antagonist), R-propranolol (5-HT1A/1B receptor antagonist), or racemic propranolol in both male and female rats. ED1 increased Fos expression in DH, LC, and DR, and DH Fos was decreased by systemic S-propranolol. Based on these results, we investigated the effects of blocking 5-HT and ?-adrenoceptor transmission in DH on drug seeking during ED1 by infusing a cocktail of WAY100635 plus GR127935 (5-HT1A/1B receptor antagonists), betaxolol plus ICI-118?551 (?1 and ?2 antagonists), or S-propranolol alone. In males, WAY100635/GR127935 was most effective in reducing drug-seeking on ED1, whereas betaxolol/ICI-118?551 was ineffective. In contrast, S-propranolol was most effective in females in reducing drug seeking on ED1, and WAY100635/GR127935 and betaxolol/ICI-118?551 were each partially effective. Our results indicate that drug seeking during initial abstinence involves 5-HT and ?-adrenergic signaling in female DH, but only 5-HT signaling in male DH.

SUBMITTER: Kohtz AS

PROVIDER: S-EPMC5399231 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Cocaine Seeking During Initial Abstinence Is Driven by Noradrenergic and Serotonergic Signaling in Hippocampus in a Sex-Dependent Manner.

Kohtz Amy S AS Aston-Jones Gary G

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20160812 2

There is evidence for sex differences in cocaine addiction from both clinical and preclinical studies. In particular, preclinical studies indicate that females may be more sensitive than males to stress-induced drug seeking. The dorsal hippocampus (DH) is prominently involved in the stress response, as are the locus coeruleus norepinephrine (LC-NE) and dorsal raphe serotonin (DR 5-HT) systems. Moreover, DH receives strong inputs from LC-NE and DR 5-HT neurons. We hypothesized that the stress ass ...[more]

PMID: 27515792

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Project description:ObjectivePeople with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert.MethodsHigh-performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α-syn deposition) and six age-matched controls were tested.ResultsPD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups.InterpretationThese results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced PD with dementia.

Project description:Clinical reports suggest that females diagnosed with substance use disorder experience enhanced relapse vulnerability compared with males, particularly during stress. We previously demonstrated that a stressor (footshock) can potentiate cocaine seeking in male rats via glucocorticoid-dependent cannabinoid type-1 receptor (CB1R)-mediated actions in the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the influence of biological sex on stress-potentiated cocaine seeking. Despite comparable self-administration and extinction, females displayed a lower threshold for cocaine-primed reinstatement than males. Unlike males, footshock, tested across a range of intensities, failed to potentiate cocaine-primed reinstatement in females. However, restraint potentiated reinstatement in both sexes. While sex differences in stressor-induced plasma corticosterone (CORT) elevations and defensive behaviors were not observed, differences were evident in footshock-elicited ultrasonic vocalizations. CORT administration, at a dose which recapitulates stressor-induced plasma levels, reproduced stress-potentiated cocaine-primed reinstatement in both sexes. In females, CORT effects varied across the estrous cycle; CORT-potentiated reinstatement was only observed during diestrus and proestrus. As in males, CORT-potentiated cocaine seeking in females was localized to the PrL-PFC and both CORT- and restraint-potentiated cocaine seeking required PrL-PFC CB1R activation. In addition, ex vivo whole-cell electrophysiological recordings from female layer V PrL-PFC pyramidal neurons revealed CB1R-dependent CORT-induced suppression of inhibitory synaptic activity, as previously observed in males. These findings demonstrate that, while stress potentiates cocaine seeking via PrL-PFC CB1R in both sexes, sensitivity to cocaine priming injections is greater in females, CORT-potentiating effects vary with the estrous cycle, and whether reactivity to specific stressors may manifest as drug seeking depends on biological sex.

Dataset Information

Cocaine Seeking During Initial Abstinence Is Driven by Noradrenergic and Serotonergic Signaling in Hippocampus in a Sex-Dependent Manner.

Publications

Cocaine Seeking During Initial Abstinence Is Driven by Noradrenergic and Serotonergic Signaling in Hippocampus in a Sex-Dependent Manner.

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